HPE Drug stability: What do we need to know? | Page 6

which is the reason why reaction rates increase and shelf-life decreases with increasing temperature. Hydrolysis Hydrolysis is cleavage of chemical bonds, such as ester and lactone bonds, by the addition of water. It is the most common drug degradation pathway in aqueous solutions but hydrolysis also occurs in solid dosage forms in the presence of moisture. Acyl groups (for example, esters, lactones, amides and lactams) are the most common substrates that are prone to hydrolysis, followed by imines and alkyl halides. Hydrolysis is frequently catalysed by buffer salts and other excipients used in drug preparation. Thus, excipients are carefully selected with regard to their effect on the shelf-life of the drug product. 4,5 Oxidation Most drugs (that is, APIs) are in their reduced form, and oxygen, which participates in most oxidative processes, is abundant in the environment. Oxidation is a loss of electrons or an increase in the oxidation state. Consequently, drug oxidation is a common reason for decreased product shelf-lives. Oxidative reactions proceed through free radicals or free radical-like pathways. Metal ions and light are known to catalyse oxidative drug degradation. Steroids, most tricyclic compounds and sulfhydryl compounds are susceptible to oxidation. Oxidative reactions can be reduced by removal of oxygen from the dosage forms, pH adjustments, using chelating agents to complex metal ions, addition of antioxidants, and exclusion of light. 4 Stability of parenteral solutions Parenteral solutions are generally clear aqueous solutions consisting of dissolved API and excipients. They must be sterile and pyrogen-free, isotonic solutions and free from visible particulate matter. Whenever possible, their pH should be close to the pH of normal blood plasma or 7.35–7.45 (that is, physiologic pH). In some cases, it is necessary to deviate somewhat from physiologic pH due to solubility and/or stability issues, and there are products on the market with pH as low as 2.5 (morphine sulfate injection) and as high as 12 (phenytoin injection). However, such large deviations from physiologic pH can cause discomfort upon administration. In some cases, parenteral solutions of poorly soluble drugs are milky emulsions (for example, propofol injections) or contain relatively high concentrations of organic solvents such as propylene glycol (for example, diazepam) but these are exceptions. Example The anticancer drug melphalan is an alkyl halide that is rapidly hydrolysed and somewhat poorly soluble in aqueous solutions. It is a base with maximum solubility and chemical stability (t 90 ≈ 24 hours) at pH below 1. The solubility decreases and rate of hydrolysis increases with increasing pH. At physiologic pH, the aqueous solubility of melphalan is about 0.05mg/ml. Due to its rapid hydrolysis (that is, a very short t 90 ) the drug must be marketed as sterile powder that is dissolved in normal saline before injection. In the marketed product (Evomela ® ) sulfobutyl ether β-cyclodextrin is used to increase the aqueous solubility and stability of the drug. The shelf-life of the reconstituted solution is 24 h at 5°C and 1 h at room temperature. 6 The physical and chemical stability can be reduced when two or more parenteral solutions are combined. Such changes are frequently referred 6 | 2019 | hospitalpharmacyeurope.com TABLE 3 The main degradation pathways Degradation pathway Example Drug Hydrolysis Ester Aspirin Lactam Benzylpenicillin Oxidation OH-groups Ascorbic acid Isomerisation Stereoisomers Tetracycline Photochemical degradation Photo/oxidation Piroxicam Dehydration Prostaglandin E 2 Polymerisation Ampicillin to as incompatibilities. For example, dextrose (glucose) catalyses hydrolytic degradation of b-lactam antibiotics, thereby shortening the drug shelf-life. Ampicillin has approximately 12-times longer shelf-life in isotonic saline (aqueous 0.9% w/v NaCl solution) than in aqueous 5% (w/v) dextrose solution. 7 Likewise, the physical stability due to drug precipitation can occur when drugs that have pH- dependent solubility (such as melphalan) are mixed with other parenteral solutions.